Steroidal Dihydropyridone Hybrids: Design, Synthesis, and In Silico Evaluation Toward Voltage‐Gated Calcium Channel

The design of hybrid molecules constitutes a valuable strategy for the development of compounds with improved or novel biological properties. This work describes the synthesis and characterization of novel steroid–3,4‐dihydro‐2(1 H )‐pyridone (DHPo) hybrids, obtained by a multicomponent reaction. Three different steroid skeletons—epiandrosterone, dehydroepiandrosterone, and pregnenolone—were functionalized to generate β‐ketoester intermediates, which were subsequently coupled with aromatic aldehydes and Meldrum's acid to give rise to six novel steroid–DHPo hybrids. The compounds were fully characterized by spectroscopic and analytical techniques. Their structural features were supported by DFT calculations, minimum energy geometries were reported, and their stereoelectronic effects and molecular properties were studied. The vasorelaxant potential of the hybrids was evaluated by molecular docking simulations on the voltage‐gated calcium (CaV) channel. All derivatives showed higher binding affinities than commercially available drugs, with the meta ‐substituted hybrids standing out as the most promising. These results suggest that the incorporation of the steroidal backbone favors ligand‐receptor interactions and may contribute to vasorelaxant activity.